Update on Management of Symptomatic Carotid Stenosis

Carotid artery stenosis (CAS) is one of the leading causes of cerebral ischemia and stroke.7 When plaque builds up in the internal carotid artery, it blocks blood flow to the brain. Oftentimes, this condition only comes to light after a patient experiences a stroke or stroke-like symptoms. When this occurs, cholesterol-lowering medications and blood thinners can help to increase blood flow to the brain. However, if the plaque is so large that it severely narrows the lumen of the artery, surgery may be required to restore blood flow to the brain. Patients with severe stenosis can undergo procedures such as carotid endarterectomies (CEA), stenting, and transcarotid artery revascularization (TCAR) for this purpose. In this review, we discuss these procedures and which patients warrant which type of intervention. We look at the pathophysiology of internal carotid artery stenosis and current treatment options, while highlighting emerging treatment options. This review aims to increase understanding of the management of symptomatic carotid artery stenosis as well as provide a groundwork for more innovative treatments.


Introduction
Carotid artery stenosis (CAS) is one of the leading causes of cerebral ischemia and stroke.[68]This stenosis may or may not be symptomatic.When it is symptomatic it can cause symptoms such as hemiplegia, dysphasia, amaurosis fugax, or vision loss.[7] As of now, one of the best ways to manage symptomatic carotid artery stenosis is by surgical interventions such as carotid endarterectomies (CEA) and transcarotid artery revascularization (TCAR).The other option is angioplasty with stent placement, which can manage symptoms.Lifestyle changes such as quitting smoking or medications such as statins, antiplatelet agents, and antihypertensives can also improve outcomes.[14] Evidence Acquisition Epidemiology of Carotid Artery Stenosis-The prevalence of carotid artery stenosis varies with the population being studied as well as the criteria that is used.When stenosis is less than 50% as measured by carotid ultrasound, the prevalence of carotid artery stenosis was 7% in women and 9% in men.[28] Prevalence of carotid artery stenosis was evaluated to be 11% in individuals with a high risk of atherosclerosis, 18% in those with a high risk of cardiac disease, and 60% in those with a high risk of acute stroke.[69,72] When stenosis is greater than 50%, the prevalence of carotid artery stenosis is 5.9% with coronary artery diseasec [82] When stenosis is greater than 70%, the prevalence of carotid artery stenosis is 2.1% with coronary artery disease.[82] The prevalence of coronary artery disease in patients with carotid stenosis can be as high as 77%.[85] The prevalence of carotid artery stenosis is higher in men than in women, at 8.8% and 5.0% respectively.[99] Additionally, the risk of carotid artery stenosis increased with age, a higher level of low-density lipoprotein cholesterol (LDL-C), a higher systolic blood pressure (SBP), and a higher fasting blood glucose.[99] Lastly, the risk of having a cerebrovascular event increased by 26% for every 10% increase in the degree of carotid stenosis.[56] This shows that coronary artery disease is a key factor in the development of carotid artery stenosis and it plays a vital role in the treatment of it as well.

Pathophysiology of Carotid Artery Stenosis
Carotid artery stenosis is caused by atherosclerosis, or an area of thickened plaque, on the arterial wall that causes the carotid artery to narrow over time.One of the biggest risk factors for this is hyperlipidemia.When there are increased levels of cholesterol in the plasma, there are changes in arterial endothelial permeability.[13] This leads to lipids, especially LDL-C, getting into the arterial wall.[13] Monocytes stick to the endothelial cells expressing adhesion molecules and move into the subendothelial space, where they transform into macrophages.[13] LDL particles then become chemoattractants, leading to more cholesterol buildup.[13] This eventually leads to plaque formation, which causes the vessel to narrow.
When this process occurs in the carotid artery, it can lead to serious complications.Even shear stress or disturbed flow through the artery can prompt the aforementioned endothelial cell changes and damage.These changes can be induced by hypertension, dyslipidemia, diabetes mellitus, and cigarette smoking.[40] Smoking is a big risk factor for stenosis.[37] For those who smoke and have diabetes mellitus, the risk is even greater for developing plaques.[38] Endothelial cell dysfunction leads to inflammatory cells accumulating, smooth muscle cells proliferating, and various cytokines and chemokines to be released, boosting the plaque and leading to further vessel narrowing.[98] Plaques in the carotid artery are typically composed of a fibrous cap covering a lipid core and inflammatory cells.[98] When this plaque ruptures or a thrombus forms from this plaque, it leads to cerebral infarction.These plaques can be stable and asymptomatic or they can be unstable, leading to acute coronary syndromes.If a plaque is prone to rupturing, it is known as an unstable or vulnerable plaque.Vulnerable plaques have active inflammation, substantial accumulation of macrophages, a thin fibrous cap with a large lipid core, denudation of the endothelium with platelet aggregation, and severe stenosis.[98] Vulnerable plaques also tend to be noncalcified whereas stable plaques tend to be calcified.[76] Stable, calcified plaques are more often associated with transient ischemic attacks (TIAs) whereas unstable, non-calcified plaques are more often associated with stroke.[90] Most patients with carotid stenosis are asymptomatic until the artery severely narrows or a clot forms.This results in a decrease or even block of blood flow to the brain, so the patient will have symptoms of a transient ischemic attack.[26] The symptoms will look like a stroke and they can include weakness or numbness on one side of the body, aphasia, facial droop, and diplopia among other vision impairments.[54] However, these symptoms will resolve within 24 hours.
Risk factors for carotid artery stenosis include older age, hypertension, and smoking.Being older can lead to increased risk for CAS, possibly due to the increasing stiffness of the walls of blood vessels.[67] High blood pressure can lead to more cholesterol deposits in the arteries, increasing the risk of plaque formation and rupture.[80] Smoking harms the endothelium of blood vessels, which makes it easier for cholesterol to deposit and form a plaque.[80] Moreover, an individual who currently smokes or used to smoke has more than a 6-fold risk of developing atherosclerotic carotid stenosis than those who do not and have not smoked.[95] Evidence Synthesis Current Treatments for Symptomatic Carotid Artery Stenosis-Surgical interventions for symptomatic carotid artery stenosis are carotid endarterectomy (CEAs), carotid artery stenting, or transcarotid artery revascularization (TCAR).Carotid endarterectomy (CEA) is performed in order to decrease the risk of stroke in a patient with known cerebrovascular atherosclerotic disease.In CEAs, plaque and potential embolic material are removed from the carotid artery, which improves blood flow.[23] Afterwards, the artery is reconstructed.Carotid artery stenting involves guiding a catheter through the artery, then inserting a stent into the artery so that it keeps the artery from narrowing again.[74] Angioplasty involves inserting a catheter with an inflatable balloon through the artery and then inflating the balloon once it gets to the part of the artery that is too narrow.[18] By doing this, the atherosclerotic plaque is pushed against the wall, which improves blood flow to that area again.Carotid artery stenting and angioplasty are typically used for moderate stenosis and CEA for severe stenosis of the carotid artery.[91] In 2014, the American Heart Association/American Stroke Association (AHA/ASA) released guidelines for the treatment of symptomatic carotid artery stenosis.[42] The recommendations read as follows: 42"For patients with a TIA or ischemic stroke within the past 6 months and ipsilateral severe (70%-99%) carotid artery stenosis as documented by noninvasive imaging, CEA is recommended if the perioperative morbidity and mortality risk is estimated to be <6% (Class I; Level of Evidence A).For patients with recent TIA or ischemic stroke and ipsilateral moderate (50%-69%) carotid stenosis as documented by catheter-based imaging or noninvasive imaging with corroboration (eg, magnetic resonance angiogram or computed tomography angiogram), CEA is recommended depending on patient-specific factors, such as age, sex, and comorbidities, if the perioperative morbidity and mortality risk is estimated to be <6% (Class I; Level of Evidence B).When the degree of stenosis is <50%, CEA and CAS are not recommended (Class III; Level of Evidence A)." 42 See Table I for more details on the recommendations from the AHA/ASA.Moreover, 94% of guidelines for symptomatic carotid artery stenosis endorsed CEA for individuals with about 50% to 99% average-CEA-risk symptomatic carotid artery stenosis, 58% endorsed stenting, and 27% opposed stenting1,69.For individuals who are at a high risk for CEA due to comorbidities, vascular anatomy, or other reasons, 82% of guidelines endorsed stenting [1,69].
Approximately 15% of ischemic strokes are due to acute tandem occlusion in the proximal (cervical) internal carotid artery and concomitant thromboembolism involving the distal (intracranial) internal carotid artery or the ipsilateral middle cerebral artery.[70] This necessitates revascularization with balloon angioplasty and stenting followed by thromboembolectomy using an anterograde or retrograde approach.[70] Intracranial mechanical thromboembolectomy followed by angioplasty and/or stenting of the proximal occlusion, or vice versa, is often used3.Whether the extracranial or intracranial approach was done first, it was shown that there were no statistically significant differences in revascularization, intracranial hemorrhage, outcomes, or mortality within the first 90 days.[94] This also raises the question as to whether angioplasty is enough or if stenting should be done as well.The problem here is that there is an increased risk of intracranial hemorrhage after stenting because dual antiplatelet therapy is the standard of care after the procedure.This was found to be the case as the risk of intracranial hemorrhage was higher in those after stenting versus after mechanical thromboembolectomy.[3] However, mono antiplatelet therapy was shown to increase the risk of transient ischemic attacks and strokes after stenting as compared to dual antiplatelet therapy.[10] Studies have also looked at the benefits of dual antiplatelet therapy with mono antiplatelet therapy and the results are summarized in table II below.
Antiplatelet therapy is a balancing act because it can reduce the risk of stroke but can also increase the risk of perioperative bleeding.[64] It was also suggested that stenting should be done with angioplasty itself was not effective enough.[48] Studies have shown that there is no statistically significant difference in patients who had stenting done versus those who only had angioplasties.[94] The studies seem to suggest that stenting can be delayed until it is deemed to be necessary.In this case, if the carotid artery becomes occluded again, it may require an emergent CEA.79According to these studies, it seems probable that the best course of action may be to perform the angioplasty, then intracranial thromboembolectomy and only stent when necessary, along with emergent CEA for extracranial occlusions.
The Society for Vascular Surgery put forth their recommendations after looking at randomized controlled trials and came up with the following guidelines: "2(1) CEA recommended over maximal medical therapy for low-risk patients; (2) is CEA recommended over transfemoral CAS for low surgical risk patients with symptomatic carotid artery stenosis of >50%; (3) the timing of carotid intervention for patients presenting with acute stroke; (4) screening for carotid artery stenosis in asymptomatic patients; and (5) the optimal sequence of intervention for patients with combined carotid and coronary artery disease."They made their recommendations based on the GRADE (grades of recommendation assessment, development, and evaluation) approach.See Table III for more details on the recommendations from the Society for Vascular Surgery.

Complications of Carotid Endarterectomy and Carotid Artery Stenting
Carotid endarterectomies are not without their risks either.Studies have shown that CEA increased the five-year risk of ischemic stroke in patients who had less than 30% stenosis of their carotid artery, had no statistically significant effect in patients with 30-49% stenosis, was beneficial in patients with 50-69% stenosis, was extremely beneficial in patients with 70-99% stenosis, and was not significantly beneficial to patients who had nearly occluded carotid arteries.[63] Both CAS and CEA are associated with high rates of failure and periprocedural stroke.51When the carotid artery is nearly completely occluded, revascularization has not been shown to reduce the risk of stroke as compared to just medical treatment.[30] It has also been shown that long-term complications are less for CAS than for CEA.[46] CEAs also come with operative complications to consider.[51,71] Wound bleeding after CEA was even more common than stroke or a myocardial infarction after CEA in patients in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) trial.[11] However, diagnosing patients with silent coronary ischemia and treating them with coronary revascularization after CEA has been shown to reduce the risk of cardiac death, myocardial infarction, and cardiovascular death compared to patients with CEA who only received the standard cardiac evaluation and care during a 3-year follow-up.43Neck hematoma was also common after CEA, especially when treated with the antiplatelet clopidogrel after surgery.[9,59] Dual antiplatelet therapy was also associated with cranial nerve injury, although transient, following CEA.[19] CEA in patients with symptomatic carotid artery stenosis is also associated with cranial nerve palsy and access site hematoma with endarterectomy.[15] Stenting provides less risk of cranial nerve injury.[91] CEA can be done with either primary closure or patches.50It was also shown that using synthetic, venous, or bovine pericardium patches did not have a significant decrease in the risk of future stroke or cranial nerve injury.88CEA is performed to save patients with severely atherosclerotic carotid artery stenosis from stroke.[81] It was also shown that an emergent CEA had decreased rates of intracerebral hemorrhage and mortality than stenting.[79] Moreover, using smaller incisions hidden within the neck crease during CEA has been shown to have better outcomes.[77] Many randomized controlled trials have been done and are currently underway to compare CEA to CAS when treating carotid artery stenosis.These studies show that CAS is often associated with periprocedural stroke and CEA is often associated with myocardial infarction.[16,46,47] It is risky to do CAS in patients who are older than 70 years of age.25However, some studies have shown that this extra risk is mainly attributable to an increase in minor, non-disabling strokes occurring in patients who are more than 70 years of age.[61] Studies show that discontinuing antiplatelet therapy, resistance to antiplatelet therapy, and thrombotic disorders are the main culprits for post-CAS thrombosis.60 CAS also can lead to prolonged hypotension and bradycardia, especially in patients with increased narrowing of the carotid artery.[31] However, CAS is preferred when CEA is contraindicated.For example, patients who have a "hostile neck" from previous surgery or who do not tolerate anesthesia well may opt for CAS.[20] Regardless of whether the patient underwent a CAS or CEA, no statin use was associated with a higher risk of in-hospital stroke or death and 5-year mortality as compared to those who did use a statin afterwards.[6] Outside of the periprocedural period, carotid stenting was shown to be just as effective as CEA when it came to preventing future strokes.[61] What is even more interesting is that a recent study actually found that high hospital volume and high operator volume decreased the risk of procedural death and stroke after CEA and CAS.[66]

Restenosis
Restenosis is of the utmost importance to consider when looking at CEA versus CAS.In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) trial, restenosis was found to have a fourfold increase in the risk of having a stroke.[45] However, when looking at patients who had CAS or CEA, they both had similar incidences of 70% or greater restenosis.[45] Studies that looked at perioperative and 1-year outcomes between patients who received either CAS or CEA also showed no significant differences.[8] It is not an exact comparison though because CEA is typically done for those who are more critically ill than those who only need CAS.It was also found that those who underwent CAS after an unsuccessful CEA, ipsilateral neck surgery, or radiation had higher rates of restenosis.[58]

Transcarotid Artery Revascularization (TCAR)
TCAR is similar to CEA, but it can be done through a small incision at the neckline instead of a bigger incision at the neck.[49] A tube is then inserted into the carotid artery while diverting blood flow away from the brain so that plaque does not travel up to the brain while the procedure is going on.[96] Essentially, the flow reversal protects against embolism.[21,33] This flow reversal helps make TCAR neuroprotective and unlike other stenting procedures.[84] The blood is then filtered and a stent is placed in the carotid artery to bolster its integrity and prevent future clot formation.This procedure is beneficial for those who have a higher risk of having a stroke.[92] TCAR is beneficial when stenting the cervical internal carotid artery, especially since this area tends to be stroke-prone.[65] That said, outcomes are best if flow reversal time is minimized as much as possible; studies suggest a clinical cutoff time of 10 minutes.[62] TCAR is not only less invasive, but it also can match the stroke hazard of CEA in standard risk populations.[53] Moreover, the results of the Safety and Efficacy Study for Reverse Flow Used During Carotid Artery Stenting Procedure (ROADSTER) multicenter trial shows that the ENROUTE Transcarotid Neuroprotection System is safe and can prevent stroke during CAS, with a stroke rate of 1.4%, which is the lowest reported to date.44 Thirty days post-TCAR, no major stroke, myocardial infarction, or death occurred in a study that was done as well.5However, more recent studies have shown that TCAR is better in the perioperative period for high-risk patients and that in the long-term, there were no significant differences in stroke or survival between groups of patients who had TCAR and CEA or TCAR and TFCAS.52On the other hand, a study done in the United States and Europe showed that patients from ROADSTER-2 trial with risk factors such as re-stenosis or radiation injury had no perioperative myocardial infarction or stroke and that in the year following surgery, there was a low stroke and death rate.[41] TCAR is a safe and effective way to approach carotid artery stenosis.[17] Another study also found no significant association between intolerance to flow reversal and comorbidities including "diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, prior myocardial infarction or angina, pre-operative CAS-related symptoms, prior stroke, prior CAS or CEA, prior neck radiation, tandem stenosis, high cervical stenosis, or hostile neck."87The same study found a significant association only with chronic obstructive pulmonary disease and contralateral carotid artery occlusion.This was corroborated by another study that found that TCAR in patients considered to have too hostile necks for CEA was not associated with increased intraoperative complexity or postoperative morbidity.[86] Studies have shown that TCAR led to a lower rate of stroke and death in the hospital after the procedure.[75] In addition to that, TCAR has been shown to be effective for older adults who are at a higher risk without perioperative cerebral ischemic event, MI, or death (Ghamraoui and Ricotta, 2020).The same finding held when looking at older adults 1 year after their TCAR procedure.57Lastly, using somatosensoryevoked potential (SSEP) and electroencephalograms (EEG) during TCARs can improve clinical decision-making for thrombosis versus vasospasm after placing stents.[36] TCAR is a premier approach to carotid revascularization, especially for patients who are at a high risk for stroke, cranial nerve injury, or cardiovascular events.[21,83] Studies looking at the differences between males and females in outcomes when looking at ipsilateral stroke, in-stent thrombosis, conversion to CEA, and death after TCAR found no statistically significant difference among them.34However, if a patient has already experienced a TIA or stroke, it was found that CEA resulted in lower rates of stroke post-operatively when compared to TCAR.[27] However, most studies overall have shown that TCAR is a safe and effective method to revascularization, substantially due to its low rates of periprocedural stroke and cranial nerve injury.[73]

Emerging Innovation
There are many novel ways of approaching carotid artery stenosis.A surgical technique that was recently tried was carotid endarterectomy (CEA) with auto-arterial remodeling of bifurcation of the common carotid artery (ARBCCA).The study looked at the difference between a classic CEA and ARBCCA and found that it does not have a significant difference in post-operative development of hypertension but the number of cases of restenosis greater than 50% during the 2-year follow-up was 4% for the ARBCCA group, compared to 12% cases in the classic CEA.[35] Staged angioplasty (SAP) is a two-arm version of CAS and it has been proven to prevent hyperperfusion-induced intracerebral hemorrhage (HICH) in patients who have preocclusive stenosis (90%-99%) and poor collateral compensation.[97] Sonolysis has also been tried to break apart thrombi during CEA and CAS and it was found that this can reduce the risk of new brain ischemic lesions.[78] When it comes to medications, it has been shown that anticoagulative agents before surgery or while awaiting CEA can prevent cerebral ischemic events when compared to antiplatelet agents alone.[55] Other ideas for innovative ways to manage carotid artery stenosis include enhanced embolic protection devices and dual-layered stents.[93] A clinical trial is currently looking at using the Xact Carotid Artery Stent and emboshield distal protection system with bivalirudin for anticoagulation in treating internal carotid artery stenosis.[24] Current clinical trials are also testing the use of evolocumab on carotid artery atherosclerotic plaques to reduce LDL-cholesterol before CEA.4Some clinical trials are also looking at abciximab to see if it can reduce the rate of recurrent ischemic strokes before and during CEA when compared with aspirin.[12] Clinical trials are also underway to assess the effect of anti-PD-1 mAbs (PD-1 immune checkpoint blockades) on the progression of atherosclerotic carotid plaques.[89]

Conclusions
Symptomatic carotid artery stenosis can be treated in many ways.The current literature vouches primarily for the use of CEA or TCAR for treatment, especially when the vessel has a greater degree of stenosis.TCAR and CEA have similar outcomes in terms of death or stroke 1 year after the respective procedure.[22] TCAR has a similar prognosis to CEA and can be performed without running the risk of myocardial infarction.[29] Here, we reviewed the literature on carotid artery stenosis, CAS, CEA, TCAR, as well as emerging innovation to provide support when making clinical decisions for treatment.For lesser degrees of stenosis, CAS is often performed and CEA is only done if the need arises.Most importantly, it is vital to always tailor treatment to each patient's condition and their unique needs.Further studies regarding treatment for carotid artery stenosis need to be conducted before we can definitively outline a proper path for treatment.

Table I :
Recommendations for Interventional Approaches for Patients with Carotid Artery Stenosis

Recommendations for Interventional Approaches for Patients with Carotid Artery Stenosis 42 Risk Factor Recommendations from the AHA/ASA Class/Level of Evidence
catheter-based imaging or noninvasive imaging with corroboration (eg, magnetic resonance angiogram or computed tomography angiogram) CEA is recommended depending on patient-specific factors, such as age, sex, and comorbidities, if the perioperative morbidity and mortality risk is estimated to be <6% Class I; Level of Evidence B The degree of stenosis is <50% CEA and CAS are not recommended Class III; Level of Evidence A Symptomatic patients at average or low risk of complications associated with endovascular intervention when the diameter of the lumen of the ICA is reduced by >70% by noninvasive imaging or >50% by catheter-based imaging or noninvasive imaging with corroboration and the anticipated rate of periprocedural stroke or death is <6% CAS is indicated as an alternative to CEA Symptomatic severe stenosis (>70%) in whom anatomic or medical conditions are present that greatly increase the risk for surgery or when other specific circumstances exist such as radiation-induced stenosis or restenosis after CEA CAS is reasonable Class IIa; Level of Evidence B Patients with a recent (within 6 months) TIA or ischemic stroke ipsilateral to a stenosis or occlusion of the middle cerebral or carotid artery EC/IC bypass surgery is not recommended Class III; Level of Evidence A Patients with recurrent or progressive ischemic symptoms ipsilateral to a stenosis or occlusion of a distal (surgically inaccessible) carotid artery, or occlusion of a mid-cervical carotid artery after institution of optimal medical therapy EC/IC bypass usefulness is considered investigational Class IIb; Level of Evidence C All patients with carotid artery stenosis and a TIA or stroke Optimal medical therapy, which should include antiplatelet therapy, statin therapy, and risk factor modification Class I; Level of Evidence A